This invention relates to new amide compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
Some aminopiperazine derivatives have been known as useful anti-amnesia or anti-dementia agents, for example, in PCT International Publication Nos. WO 91/01979 and WO 98/35951.
This invention relates to new amide compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to new amide compounds and pharmaceutically acceptable salts thereof which have the potentiation of the cholinergic activity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, and to a method for the treatment and/or prevention of disorders in the central nervous system for mammals, and more particularly to method for the treatment and/or prevention of amnesia, dementia (e.g., senile dementia, Alzheimer""s dementia, dementia associated with various diseases such as cerebral vascular dementia, cerebral post-traumatic dementia, dementia due to brain tumor, dementia due to chronic subdural hematoma, dementia due to normal pressure hydrocephalus, post-meningitis dementia, Parkinson""s disease type dementia, etc.), and the like. Additionally, the object compound is expected to be useful as therapeutical and/or preventive agents for schizophrenia, depression, stroke, head injury, nicotine withdrawal, spinal cord injury, anxiety, pollakiuria, incontinence of urine, myotonic dystrophy, attention deficit hyperactivity disorder, excessive daytime sleepiness (narcolepsy), Parkinson""s disease or autism.
One object of this invention is to provide new and useful amide compounds and pharmaceutically acceptable salts thereof which possess the potentiation of the cholinergic activity.
Another object of this invention is to provide processes for preparation of said amide compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said amide compounds and pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a therapeutic method for the treatment and/or prevention of aforesaid diseases in mammals, using said amide compounds and pharmaceutically acceptable salts thereof.
The amide compounds of this invention are new and can be represented by the following general formula [I]: 
wherein R1 is acyl,
R2 is lower alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower alkenyloxy, lower alkenylamino, lower alkynyl, lower alkynyloxy, lower alkynylamino, cyclo(lower)alkyl, cyclo(lower)alkyloxy, cyclo(lower)alkylamino, aryl, aryloxy, arylamino, a heterocyclic group or amino substituted with a heterocyclic group, each of which may be substituted with suitable substituent(s); or acyl;
A is a single bond, 
xe2x80x83or xe2x80x94SO2xe2x80x94,
E is lower alkylene optionally substituted with suitable substituent(s),
X is CH or N,
Y is a single bond, lower alkylene or 
wherein R5 is hydrogen, lower alkyl, substituted-lower alkyl, an N-protective group, aryl, acyl or a heterocyclic group),
Q is xe2x80x94CH2xe2x80x94, 
xe2x80x83xe2x80x94SO2xe2x80x94 or xe2x80x94Nxe2x95x90CHxe2x80x94, and
R3 and R4 are each hydrogen or lower alkyl, or are taken together to form lower alkylene optionally condensed with a cyclic hydrocarbon or a heterocyclic ring,
provided that when X is N,
then 1) Y is a single bond, and
Q is xe2x80x94CH2xe2x80x94, 
xe2x80x83or xe2x80x94SO2xe2x80x94, or
2) Y is lower alkylene,
and pharmaceutically acceptable salts thereof. The object compound [I] or its salt can be prepared by processes as illustrated in the following reaction schemes. 
wherein R1, R2, R3, R4, A, E, Q, X and Y are each as defined above,
Qa is 
xe2x80x83or xe2x80x94SO2xe2x80x94,
R6 is aryl which may be substituted with suitable substituent(s), or pyridyl,
R7 is lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, aryl or a heterocyclic group, each of which may be substituted with suitable substituent(s),
Ra5 is an N-protective group,
Ra2 is lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, aryl or a heterocyclic group, each of which may be substituted with suitable substituent(s),
Qb is xe2x80x94CH2xe2x80x94, 
xe2x80x83or xe2x80x94SO2xe2x80x94,
Za is an acid residue,
Qc is 
Rb5 is lower alkyl,
Zb is an acid residue,
Zc is an acid residue, and
Ya is lower alkylene.
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
The lower moiety in the term xe2x80x9clower alkenylxe2x80x9d, xe2x80x9clower alkenyloxyxe2x80x9d, xe2x80x9clower alkenylaminoxe2x80x9d, xe2x80x9clower alkynylxe2x80x9d, xe2x80x9clower alkynyloxyxe2x80x9d and xe2x80x9clower alkynylaminoxe2x80x9d is intended to mean a group having 2 to 6 carbon atoms.
The lower moiety in the terms xe2x80x9ccyclo(lower)alkylxe2x80x9d, xe2x80x9ccyclo(lower)alkyloxyxe2x80x9d and xe2x80x9ccyclo(lower)alkylaminoxe2x80x9d is intended to mean a group having 3 to 6 carbon atoms.
Suitable xe2x80x9clower alkylxe2x80x9d and lower alkyl moiety in the terms xe2x80x9csubstituted-lower alkylxe2x80x9d, xe2x80x9car(lower)alkylxe2x80x9d, xe2x80x9chalo(lower)alkylxe2x80x9d, xe2x80x9clower alkylaminoxe2x80x9d, xe2x80x9clower alkylsilylxe2x80x9d, xe2x80x9clower alkylthioxe2x80x9d and xe2x80x9clower alkylsulfonylxe2x80x9d may be a straight or branched C1-C6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, ethylpropyl, hexyl or the like, in which preferable one is methyl.
Suitable xe2x80x9clower alkenylxe2x80x9d and lower alkenyl moiety in the terms xe2x80x9clower alkenyloxyxe2x80x9d and xe2x80x9clower alkenylaminoxe2x80x9d may be a straight or branched C2-C6 alkenyl such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, isopropenyl, butadienyl, pentadienyl, hexadienyl or the like, in which preferable one is ethenyl, propentyl or butadienyl.
Suitable xe2x80x9clower alkynylxe2x80x9d and lower alkynyl moiety in the terms xe2x80x9clower alkynyloxyxe2x80x9d and xe2x80x9clower alkynylaminoxe2x80x9d may be a straight or branched C2-C6 alkynyl such as ethynyl, propargyl, butynyl or the like, in which preferable one is ethynyl.
Suitable xe2x80x9ccyclo(lower)alkylxe2x80x9d and cyclo(lower)alkyl moiety in the terms xe2x80x9ccyclo(lower)alkyloxyxe2x80x9d and xe2x80x9ccyclo(lower)alkylaminoxe2x80x9d may be cyclo(C3-C6)alkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in which preferable one is cyclopropyl.
Suitable xe2x80x9carylxe2x80x9d and aryl or ar moiety in the terms xe2x80x9car(lower)alkoxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9carylaminoxe2x80x9d, xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9caroylxe2x80x9d and xe2x80x9car(lower)alkylxe2x80x9d may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.] and the like, in which preferable one is phenyl or tolyl.
Suitable xe2x80x9car(lower)alkylxe2x80x9d may be benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and the like, in which preferable one is benzyl.
Suitable xe2x80x9clower alkylenexe2x80x9d and lower alkylene moiety in the term xe2x80x9clower alkylenedioxyxe2x80x9d may be a straight or branched C1-C6 alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, ethylethylene or the like, in which preferable one is methylene, ethylene or trimethylene.
Suitable xe2x80x9clower alkoxyxe2x80x9d and lower alkoxy moiety in the terms xe2x80x9car(lower)alkoxyxe2x80x9d and xe2x80x9chalo(lower)alkoxyxe2x80x9d may be a straight or branched C1-C6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which preferable one is methoxy or tert-butoxy.
Suitable xe2x80x9car(lower)alkoxyxe2x80x9d may be benzyloxy, phenethyloxy, phenylpropoxy, benzhydryloxy, trityloxy and the like.
Suitable xe2x80x9chalogenxe2x80x9d and halo moiety in the term xe2x80x9chalo(lower)alkylxe2x80x9d may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine, chlorine or iodine.
Suitable xe2x80x9chalo(lower)alkylxe2x80x9d may be lower alkyl substituted with one or more halogens such as chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentachloroethyl or the like, in which preferable one is trifluoromethyl.
Suitable xe2x80x9chalo(lower)alkoxyxe2x80x9d may be lower alkoxy substituted with one or more halogens such as chloromethoxy, dichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentachloromethoxy or the like, in which preferable one is trifluoromethoxy.
Suitable xe2x80x9clower alkylaminoxe2x80x9d may be mono or di (lower alkylamino) such as methylamino, ethylamino, porpylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, diisopropylamino, dipentylamino, dihexylamino, N-methylethylamino or the like, in which preferable one is dimethylamino.
Suitable xe2x80x9clower alkylsilylxe2x80x9d may be mono, di, or tri(lower)alkylsilyl such as trimethylsilyl, dimethylsilyl, triethylsilyl or the like, in which preferable one is trimethylsilyl.
Suitable xe2x80x9clower alkylenedioxyxe2x80x9d may be methylenedioxy, ethylenedioxy and the like, in which preferable one is methylenedioxy.
Suitable xe2x80x9cheterocyclic groupxe2x80x9d may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and preferable heterocyclic group may be N-containing heterocyclic group such as unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; saturated 3 to 7-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolo-pyridazinyl [e.g. tetrazolo[1,5-b]pyridazinyl, etc.], quioxalinyl, etc.;
unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.;
saturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, 1H-tetrahydropyranyl, tetrahydrofuranyl, etc.;
unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, etc.;
unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], oxazolinyl [e.g. 2-oxazolinyl, etc.], etc.;
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzofurazanyl, benzoxazolyl, benzoxadiazolyl, etc.];
unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.;
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. thiazolidinyl, etc.];
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. benzothiazolyl, benzothiadiazolyl, etc.];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms [e.g. benzofuranyl, benzodioxolyl, chromanyl, etc.] and the like.
Said xe2x80x9cheterocyclic groupxe2x80x9d may be substituted with lower alkyl as exemplified above, in which preferable one is thienyl, pyridyl, methylpyridyl, quinolyl, indolyl, quinoxalinyl, benzofuranyl or tetramethylchromanyl, and more preferable one is pyridyl.
Suitable xe2x80x9cacylxe2x80x9d may be carboxy; esterified carboxy;
carbamoyl substituted with lower alkyl, aryl, ar(lower)alkyl, arylsulfonyl, lower alkylsulfonyl or a heterocyclic group;
substituted or unsubstituted arylsulfonyl;
lower alkylsulfonyl; cyclo(lower)alkylcarbonyl;
lower alkanoyl; substituted or unsubstituted aroyl;
a heterocycliccarbonyl and the like.
The esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable one is unsubstituted lower alkoxycarbonyl and more preferable one is methoxycarbonyl or tert-butoxycarbonyl.
The carbamoyl substituted with lower alkyl may be methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-methyl-N-ethylcarbamoyl and the like.
The carbamoyl substituted with aryl may be phenylcarbamoyl, naphthylcarbamoyl, lower alkyl-substituted phenylcarbamoyl [e.g. tolylcarbamoyl, xylylcarbamoyl, etc.] and the like.
The carbamoyl substituted with ar(lower)alkyl may be benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl and the like, in which preferable one is benzylcarbamoyl.
The carbamoyl substituted with arylsulfonyl may be phenylsulfonylcarbamoyl, tolylsulfonylcarbamoyl and the like.
The carbamoyl substituted with lower alkylsulfonyl may be methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl and the like.
The carbamoyl substituted with a heterocyclic group may be one substituted with a heterocyclic group as mentioned above.
The lower alkanoyl may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like, in which preferable one is acetyl or pivaloyl.
The substituted or unsubstituted aroyl may be benzoyl, naphthoyl, toluoyl, di(tert-butyl)benzoyl, halo(lower)alkoxybenzoyl [e.g. trifluoromethoxybenzoyl, etc.] and the like, in which preferable one is benzoyl or trifluoromethoxybenzoyl.
The substituted or unsubtituted arylsulfonyl may be phenylsulfonyl, tolylsulfonyl, halophenylsulfonyl [e.g. fluorophenylsulfonyl, etc.] and the like, in which preferable one is fluorophenylsulfonyl.
The lower alkylsulfonyl may be methylsulfonyl, ethylsulfonyl and the like, in which preferable one is methylsulfonyl.
The cyclo(lower)alkylcarbonyl may be cyclo(C3-C6)-alkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl, in which preferable one is cyclopropylcarbonyl.
The heterocyclic moiety in the term xe2x80x9ca heterocycliccarbonylxe2x80x9d may be one mentioned above as a heterocyclic group.
Suitable xe2x80x9cacid residuexe2x80x9d may be halogen [e.g. fluoro, chloro, bromo, iodo], arenesulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy, etc.], alkanesulfonyloxy [e.g. mesyloxy, ethanesulfonyloxy, etc.], and the like, in which preferable one is halogen.
Suitable xe2x80x9cN-protective groupxe2x80x9d may be common N-protective group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], 9-fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, aralkyl [e.g. trityl, benzyl, etc.] or the like, in which preferable one is lower alkoxycarbonyl and more preferable one is tert-butoxycarbonyl.
Suitable xe2x80x9ccyclic hydrocarbonxe2x80x9d may be a saturated or unsaturated cyclic hydrocarbon such as cyclopentane, cyclohexane, benzene, naphthalene, indan, indene or the like.
Suitable xe2x80x9csubstituted-lower alkylxe2x80x9d may be lower alkyl substituted with halogen, aryl, acyl, lower alkoxy, aryloxy and the like, in which preferable one is benzyl.
Suitable xe2x80x9cheterocyclic ringxe2x80x9d may be one which is a heterocyclic group, as mentioned above, added by hydrogen.
Preferred xe2x80x9cacylxe2x80x9d for R1 may be lower alkanoyl; lower alkoxycarbonyl; aroyl optionally substituted with halo(lower)alkoxy; arylsulfonyl optionally substituted with halogen; lower alkylsulfonyl; or cyclo(lower)alkylcarbonyl, in which more preferable one is acetyl, pivaloyl, methoxycarbonyl, tert-butoxycarbonyl, benzoyl, trifluoromethoxybenzoyl, fluorophenylsulfonyl, methylsulfonyl or cyclopropylcarbonyl.
Preferred xe2x80x9csuitable substituentxe2x80x9d as the substituent of lower alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower alkenyloxy, lower alkenylamino, lower alkynyl, lower alkynyloxy, lower alkynylamino, cyclo(lower)alkyl, cyclo(lower)alkyloxy, cyclo(lower)alkylamine, aryl, aryloxy, arylamino, a heterocyclic group or amino substituted a heterocyclic group for R2 may be halo(lower)alkyl, halo(lower)alkoxy, lower alkenyl, lower alkynyl, lower alkylamino, acylamino, acyl, lower alkylsilyl, lower alkoxy, aryl, lower alkylenedioxy, acyloxy, hydroxy, nitro, amino, cyano, halogen, aryloxy, lower alkylthio and the like.
Preferred xe2x80x9caryl which may be substituted with suitable substituent(s)xe2x80x9d for R2 may be aryl optionally substituted with halogen, in which more preferable one is fluorophenyl.
Preferred xe2x80x9carylamino which may be substituted with suitable substituent(s)xe2x80x9d for R2 may be arylamino optionally substituted with halogen, in which preferable one is phenylamino or fluorophenylamino.
Preferred xe2x80x9caryloxy which may be substituted with suitable substituent(s)xe2x80x9d for R2 may be aryloxy optionally substituted with halogen, in which preferable one is fluorophenoxy.
Preferred xe2x80x9clower alkylenexe2x80x9d for Y may be methylene.
Preferred xe2x80x9clower alkylxe2x80x9d for R5 in Y may be methyl.
Preferred xe2x80x9cN-protective groupxe2x80x9d for R5 in Y may be tert-butoxycarbonyl.
Preferred xe2x80x9csuitable substituentxe2x80x9d as the substituent of lower alkylene for E may be oxo, lower alkyl, hydroxy(lower)alkyl or acyl, in which more preferable one is oxo, dioxo, methyl, dimethyl, hydroxymethyl, or benzylcarbamoyl.
Preferred xe2x80x9clower alkylnexe2x80x9d for E may be methylene, ethylene or trimethylene, and more preferable one is ethylene.
Preferred xe2x80x9clower alkylxe2x80x9d for R3 and R4 may be methyl.
Preferred xe2x80x9clower alkylene which R3 and R4 are taken together to formxe2x80x9d may be ethylene or trimethylene.
Preferred xe2x80x9ca cyclic hydrocarbon with which lower alkylene is condensedxe2x80x9d may be benzene.
Preferred compound [I] is one having lower alkanoyl, lower alkoxycarbonyl, aroyl, aroyl substituted with halo(lower)alkoxy, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl substituted with halogen or cyclo(lower)alkylcarbonyl for R1, aryl, aryloxy or arylamino, each aryl of which may be substituted with halogen; pyridyl; or pyridylamino for R2, a single bond for A, ethylene for E, CH for X, 
for Y, 
for Q, and ethylene for R3 and R4 to be taken together to form, or lower alkanoyl, lower alkoxycarbonyl, aroyl, aroyl substituted with halo(lower)alkoxy, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl substituted with halogen or cyclo(lower)alkylcarbonyl for R1, aryl, aryloxy or arylamino, each aryl of which may be substituted with halogen; pyridyl; or pyridylamino for R2, a single bond for A, ethylene for E, N for X, a single bond for Y, 
for Q, and ethylene for R3 and R4 to be taken together to form.
Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts and include acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], a salt with an amino acid [e.g. aspartic acid salt, glutamic acid salt, etc.], a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.] and the like.
The processes for preparing the object compound [I] are explained in detail in the following.
The compound [Ia] or its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its reactive derivative at the carboxy or sulfo group, or a salt thereof.
Suitable salts of the compounds [Ia] and [III] may be the same as those exemplified for the compound [I].
Suitable salts of the compound [III] and its reactive derivative at the carboxy or sulfo group may be metal salt or alkaline earth metal salt as exemplified for the compound [I].
Suitable reactive derivative at the carboxy or sulfo group or the compound [III] may include an ester, an acid halide, an acid anhydride and the like. The suitable examples of the reactive derivatives may be an acid halide [e.g. acid chloride, acid bromide, etc.]; a symmetrical acid anhydride; a mixed acid anhydride with an acid such as aliphatic carboxylic acid [e.g. acetic acid, pivalic acid, etc.), substituted phosphoric acid [e.g. dialkylphosphoric acid, diphenylphosphoric acid, etc.]; an ester such as substituted or unsubstituted lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, trichloromethyl ester, etc.], substituted or unsubstituted ar(lower)alkyl ester [e.g. benzyl ester, benzhydryl ester, p-chlorobenzyl ester, etc.], substituted or unsubstituted aryl ester [e.g. phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphthyl ester, etc.], or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole, 1-hydroxy-6-chloro-1H-benzotriazole, or the like. These reactive derivatives can be optionally selected according to the kind of the compound [III] to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, acetonitrile, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvent may be used in a mixture with water.
The reaction is also preferably carried out in the presence of a conventional base such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, etc., or a mixture thereof.
When the compound [III] is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide, N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide, N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide, thionyl chloride, oxalyl chloride, lower alkoxycarbonyl halide (e.g. ethyl chloroformate, isobutyl chloroformate, etc.], 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, or the like.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
The compound [Ib] or its salt can be prepared by reacting a compound [III] or its salt with a compound [IV].
Suitable salts of the compounds [Ib] and [II] may be the same as those exemplified for the compound [I].
This reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, benzene, toluene, chloroform, methylene chloride or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
The compound [Ic] or its salt can be prepared by reacting a compound [V] or its salt with a compound [III] or its reactive derivative at the carboxy or sulfo group, or a salt thereof.
Suitable salts of the compounds [Ic] and [V] may be the same as those exemplified for the compound [I].
Suitable salts of the compound [III] and its reactive derivative at the carboxy or sulfo group may be metal salt or alkaline earth metal salt as exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
The compound [Id] or its salt can be prepared by reacting a compound [V] or its salt with a compound [IV].
Suitable salts of the compounds [Id] and [V] may be the same as those exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 2.
The compound [I] or its salt can be prepared by reacting a compound [VI] or its salt wit h a compound [VII] or its reactive derivative at the carboxy or sulfo group, or a salt thereof.
Suitable salt of the compound [VI] may be acid addition salt as exemplified for the compound [I].
Suitable salts of the compound [VII] and its reactive derivative at the carboxy or sulfo group may be metal salt or alkaline earth metal salt as exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
The compound [Ie] or its salt can be prepared by reacting a compound [VIII] or its reactive derivative at the carboxy group or sulfo group, or a salt thereof with a compound [IX] or its salt.
Suitable salts of the compounds [Ie], [VIII] and its reactive derivative at the carboxy or sulfo group may be the same as those exemplified for the compound [I].
Suitable salt of the compound [IX] may be acid addition salt as exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
The compound [If] can be prepared by reacting a compound [X] or its salt with a compound [XI].
Suitable salts of the compounds [If] and [X] may be the same as those exemplified for the compound [I].
The present reaction is preferably carried out in the presence of base such as an alkali metal [e.g. lithium, sodium, potassium, etc.], alkaline earth metal [e.g. calcium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], the hydroxide or carbonate or bicarbonate of an alkali metal or an alkaline earth metal [e.g. potassium bicarbonate, etc.] and the like.
This reaction is usually carried out in a solvent such as N,N-dimethylformamide, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or any other solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The object compound [Ig] of its salt can be prepared by subjecting a compound [If] or its salt to elimination reaction of the N-protective group.
Suitable salts of the compounds [If] and [Ig] may be acid addition salts as exemplified for the compound [I].
This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, alkylamine [e.g. methylamine, trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo-[5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.] and an acid addition salt compound [e.g. pyridine hydrochloride, etc.].
The elimination using trihaloacetic acid [e.g. richloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform, tetrachloromethane, dioxane, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ullman copper, etc.] and the like.
In case that the N-protective group is benzyl, the reduction is preferably carried out in the presence of a combination of palladium catalysts [e.g. palladium black, palladium on carbon, etc.] and formic acid or its salt [e.g. ammonium formate, etc.].
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
The compound [Ii] or its salt can be prepared by reacting a compound [Ih] or its salt with a compound [XII].
Suitable salts of the compounds [Ih] and [Ii] may be the same as those exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 7, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 7.
The compound [Ij] or its salt can be prepared by reacting a compound [II] or its salt with a compound [XIII].
Suitable salts of the compounds [Ij] and [II] may be the same as those exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 7, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 7.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
It is to be noted that the compound [I] and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) or geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixture thereof are included within the scope of this invention.
Additionally, it is to be noted that any solvate [e.g. enclosure compound (e.g. hydrate, etc.)] of the compound [I] or a pharmaceutically acceptable salt thereof is also included within the scope of this invention.
The object compound [I] and pharmaceutically acceptable salts thereof possess strong potentiation of the cholinergic activity, and are useful for the treatment and/or prevention of disorders in the central nervous system for mammals, and more particularly of amnesia, dementia (e.g., senile dementia, Alzheimer""s dementia, dementia associated with various diseases such as cerebral vascular dementia, cerebral post-traumatic dementia, dementia due to brain tumor, dementia due to chronic subdural hematoma, dementia due to normal pressure hydrocephalus, post-meningitis dementia, Parkinson""s disease type dementia, etc.) and the like. Additionally, the object compound is expected to be useful as therapeutical and/or preventive agents for schizophrenia, depression, stroke, head injury, nicotine withdrawal, spinal cord injury, anxiety, pollakiuria, incontinence of urine, myotonic dystrophy, attention deficit hyperactivity disorder, excessive daytime sleepiness (narcolepsy), Parkinson""s disease or autism.
In order to illustrate the usefulness of the object compound [I], the pharmacological data of the compound [I] is shown in the following.
Penile Erection in Rat
(This test was carried out according to a similar manner to that described in Jpn. J. Pharmacol., Vol. 64, 147-153 (1994))
(i) Method
Male Fischer 344 rats at the age of 8 weeks (n=7) were used. All rats were handled 3 minutes a day for three successive days before the tests. The rats were tested in groups of seven and various doses of the test compound were given in semi-randomized order. The test compounds were suspended in 0.5% methyl-cellulose immediately before use, and given intraperitoneally in a volume of 1 ml/kg just before the start of test. Immediately after injection, each rat was placed in a perspex box (25xc3x9725xc3x9735 cm) and its behavior was observed for 60 minutes, during which time the number of penile erections was counted. A mirror was situated behind each box to facilate of the rat. Data was expressed as a mean number.
(ii) Test Result
It is clear that the compound having the above-mentioned activity ameliorates the memory deficits (i.e. amnesia, dementia, etc.) from the description in the Journal of Pharmacology and Experimental Therapeutics, Vo. 279, No. 3, 1157-1173 (1996). Further, it is expected that the compound having the above-mentioned activity is useful as therapeutical and/or preventive agent for aforesaid diseases from some patent applications (e.g. PCT International Publication No. WO 98/27930, etc.).
For therapeutic purpose, the compound [I] and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral or parenteral administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
While the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.